tbuckley/cabot-search huggingface dataset:
Abstract 1244: Examining the differential roles of OSM and IL-6 in varying subtypes of breast cancer for novel therapeutic treatment
Authors: Cody L. Wolf, Ken Tawara, Cheryl L. Jorcyk
Journal: Cancer Research (2023)

Abstract Breast cancer remains the second leading cause of cancer-related death in women, in large part due to distant metastasis to organs such as bone, lung, liver, and brain. Our laboratory has demonstrated that the IL-6-family cytokine oncostatin M (OSM) increases circulating tumor cell (CTC) numbers and metastases to lung in vivo, and that OSM stays active when bound to proteins in the extracellular matrix, thus “bioaccumulating” in the tumor microenvironment. These published findings are supported by our results demonstrating that OSM strongly promotes expression and secretion of IL-6 from breast cancer cells. Interestingly, the increased production of IL-6 by OSM occurs only in estrogen receptor-negative (ER-) cells. It is well known that patients with ER- breast cancer, specifically triple negative breast cancer (TNBC; ER- PR- HER2-), have limited therapeutic options. However, the divergent role OSM plays in ER+ and ER- breast cancer and the mechanism by which this occurs has yet to be fully understood. Thus, we aimed to fully elucidate the difference between OSM in ER+ versus ER- breast cancer. First, we performed RNA-Seq analysis on OSM-treated human ER+ T47D cells and ER- TNBC MDA-MB-231 cells and discovered significant differences in gene expression between both cell lines upon treatment with OSM, including alteration in DNA-replication and cell cycle pathway genes. Next, to better understand the mechanism by which OSM-mediated IL-6 secretion is repressed, we utilized a computational modeling approach and evaluated the direct inhibition of STAT3 and ER to identify theoretical dimerization complex for future studies. This research aims to elucidate the unique role OSM plays in ER+ and ER- breast cancer and will provide a molecular understanding of how this occurs and will provide detailed information on which patients will benefit most from anti-OSM therapeutics. Citation Format: Cody L. Wolf, Ken Tawara, Cheryl L. Jorcyk. Examining the differential roles of OSM and IL-6 in varying subtypes of breast cancer for novel therapeutic treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1244.
Abstract 1097: Surufatinib improved the radiation sensitivity of biliary cancer growth by reprograming of TAM and anti-angiogenesis
Authors: Hong Ma, Ai Huang, Yong Xiao, Jing Yao, Ningyu Wang, Xiangping Mei, Shaoshi Wen, Xing Lv
Journal: Cancer Research (2023)

Abstract Background: Patients with Biliary tract cancer (BTC) have poor clinical outcomes. Radiation therapy is an adjunct strategy throughout biliary tract cancer treatment. The aim of the study was to explore the efficacy and mechanism of the radiosensitization of surufatinib(SF), an oral tyrosine kinase inhibitor with anti-angiogenic and immunomodulatory activities. Methods: The NOZ and TFK1 human BTC cell lines were treated with SF and/or radiation. Effects on cell viability and cell cycle progression were measured by CCK8, a clonogenic survival assay, and flow cytometry. Finally, the in vivo effect on the growth of NOZ xenografts was assessed in nude mice. F4/80, CD206, Ki67 and CD31 expression were employed in tumor samples. Results: SF inhibited the proliferation and enhanced the radiosensitivity in NOZ and TFK1 cells lines. SF combined with radiation increased cell cycle arrest in the G2/M phase compared to the other treatments in the NOZ cell line (P&amp;lt;0.05). Similarly, cell cycle arrest occurred in the TFK1 cell line, (P&amp;lt;0.05). In vivo, SF plus radiation significantly inhibited the tumor growth compared to either agent independently. Conclusions: SF significantly increased the radiosensitivity of NOZ and TFK1 cells in vitro and in vivo. Radiation combined with SF inhibited tumor proliferation, increased apoptosis, prolonged G2/M arrest. SF decreased the number of blood vessels and reprogrammed the macrophages from M2 to M1. These data support the clinical trials of biologically targeted and conventional therapies in the treatment of cancer. Citation Format: Hong Ma, Ai Huang, Yong Xiao, Jing Yao, Ningyu Wang, Xiangping Mei, Shaoshi Wen, Xing Lv. Surufatinib improved the radiation sensitivity of biliary cancer growth by reprograming of TAM and anti-angiogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1097.
Abstract 1482: Critical role of OGT-mediated novel NF-κB o-glcNAcylation in pancreatic cancer
Authors: Aishat Motolani, Matthew Martin, Benlian Wang, Guanglong Jiang, Yunlong Liu, Tao Lu
Journal: Cancer Research (2023)

Abstract Pancreatic ductal adenocarcinoma (PDAC) has one of the highest mortalities of all malignancies, with a mere 5-year survival of ~10%. However, the current first-line treatments have poor patient outcomes, highlighting the urgent need for innovative therapeutics. The nuclear factor κB (NF-κB) is a crucial transcription factor frequently activated constitutively in PDAC. It mediates the transcription of oncogenic and inflammatory genes that facilitate multiple PDAC phenotypes. Thus, a better understanding of the mechanistic underpinnings of NF-κB activation holds substantial promise in PDAC diagnosis and new therapeutics. The purpose of this study is to identify novel regulation of NF-κB, with the aim of providing new diagnostic and therapeutic strategies for PDAC. Here, we report protein O-GlcNAc transferase (OGT) - mediated NF-κB activation through novel serine O-GlcNAcylation of its p65 subunit. We show that overexpression of serine-to-alanine (S-A) mutant at the O-GlcNAcylation site impaired NF-κB nuclear translocation and transcriptional activity in PDAC cells. Moreover, these S-A p65 mutants downregulate NF-κB-target genes important to major cancer hallmarks and inhibit cellular proliferation, migration, and anchorage-independent growth of PDAC cells compared to WT-p65. Interestingly, this modification happens downstream of the inhibitor of NF-κB (IκBα) degradation. Collectively, we have identified OGT-mediated serine O-GlcNAcylation of NF-κB and determined its mechanistic and cellular function in driving PDAC phenotypes. Thus, our study holds great significance as it uncovers a brand-new strategy for PDAC diagnosis and effective therapeutics development. Citation Format: Aishat Motolani, Matthew Martin, Benlian Wang, Guanglong Jiang, Yunlong Liu, Tao Lu. Critical role of OGT-mediated novel NF-κB o-glcNAcylation in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1482.
Abstract 5284: Recurrent Middle Eastern differentiated thyroid carcinoma has worse outcome than persistent disease
Authors: Sandeep K. Parvathareddy, Abdul K. Siraj, Padmanaban Annaiyappanaidu, Nabil Siraj, Saeeda O. Ahmed, Zeeshan Qadri, Saud Azam, Khawla S. Al-Kuraya
Journal: Cancer Research (2023)

Abstract Background: Differentiated Thyroid Cancer (DTC) is the most common endocrine malignancy. Despite its excellent prognosis, recurrent and persistent disease remain major challenges after initial treatment. Although most studies have considered persistence and recurrent as a single entity, emerging studies to differentiate recurrent and persistent disease are controversial and study on recurrent and persistent DTC from Middle Eastern ethnicity is lacking. Methods: We retrospectively analyzed 1822 patients who underwent surgery ± I131 treatment for DTC with a median age of 38.9 years and median follow-up of 90 months. Results: We found a similar prevalence rate of persistent and recurrent disease (16.4% vs. 16.6%) in Middle Eastern DTC patients. Relative to patients with persistent disease, patients with recurrent disease were significantly older (median age 36.1 vs. 45.8 years; p &amp;lt; 0.0001), were more likely to have ATA high risk tumors (p &amp;lt; 0.0001) and had a higher rate of distant metastasis (p &amp;lt; 0.0001). However, structural disease had an almost similar frequency in both recurrent and persistent disease (72.2% vs 73.3%). On multivariant logistic regression analysis, both T status and N status are independent predictors for both recurrent and persistent disease. However, older age, extrathyroidal extension and the presence of distant metastasis were independent predictors of only recurrent disease. In addition, patients with recurrent disease had significantly worse overall survival (OS; p &amp;lt; 0.0001) and cancer specific survival (CSS; p &amp;lt; 0.0001), which remained significant in multivariate Cox proportional hazard model (Hazard ratio = 2.72; 95% confidence interval = 1.20 - 7.01; p = 0.0153 for OS and Hazard ratio = 5.09; 95% confidence interval = 2.10 - 15.24; p = 0.0001 for CSS). Conclusion: Although persistent and recurrent disease in Middle Eastern DTC have similar frequencies, recurrent disease had worse outcome compared to persistent disease. This has great potential clinical relevance to differentiate recurrene from persistence for therapeutic and follow-up approach for improving outcomes of DTC patients from Middle Eastern ethnicity. Citation Format: Sandeep K. Parvathareddy, Abdul K. Siraj, Padmanaban Annaiyappanaidu, Nabil Siraj, Saeeda O. Ahmed, Zeeshan Qadri, Saud Azam, Khawla S. Al-Kuraya. Recurrent Middle Eastern differentiated thyroid carcinoma has worse outcome than persistent disease. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5284.
Abstract 3343: Liquid biopsy screening tool for the earlier detection of brain tumors
Authors: Ashton G. Theakstone, Paul M. Brennan, Matthew J. Baker
Journal: Cancer Research (2023)

Abstract Background: There is a need for a rapid, cost-effective and non-invasive screening tool for the earlier detection and diagnosis of brain tumors. Serum based ATR-FTIR combined with machine learning algorithms can reliably predict which patients with symptoms will actually have a tumor on brain imaging. This technique gives a broad overall serum composition of the patient. However, an approach combining spectroscopy and specific cytokines within the serum could potentially provide a more accurate detection and permit prediction of tumor subtypes before histological diagnosis. Method: Patient serum samples (300uL) were collected prospectively from patients with a new brain tumor diagnosis, and patients without a brain tumor as non-cancer controls. Each patient was analysed using both ATR-FTIR and an electrochemical approach targeting specific cytokine markers. MMP-3, MMP-9 and osteopontin were selected from an unsupervised screening of 64 cytokines. The patients were discriminated using machine learning techniques in three approaches; spectral data alone, biomarker data alone and the combination of both spectral and biomarker data. Receiver operator characteristic (ROC) curve analysis was completed to display the discriminatory ability of each approach. Results: The spectral and biomarker data was collected for 49 patient samples (25 non-cancer, 24 GBM). All three approaches gave excellent discriminatory ability between cancer and non-cancer control patients. The spectral profiles alone had an area under the curve (AUC) of 0.958, the biomarker data alone had an AUC of 0.937 and the combination of spectral and biomarker data for each patient had an AUC of 0.975. The clinical datatset is being expanded to include more patients and this paper will discuss further patient analysis as well. Conclusion: The combination of using patient data from both the spectroscopic and electrochemical approaches improved the discrimination between cancer and non-cancer patients. The addition of specific marker information could support prioritization for brain imaging, and prediction of tumor subtype to guide pre-operative management decision-making. Citation Format: Ashton G. Theakstone, Paul M. Brennan, Matthew J. Baker. Liquid biopsy screening tool for the earlier detection of brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3343.
Abstract 2013: Oxidized anthracycline payloads induce anti-tumor immunogenic cell-death and show linker-dependent tolerability when delivered as ADCs
Authors: Joseph Z. Hamilton, Kerry Klussman, Rebecca Mahzereh, Jessica Simmons, Michelle Ulrich, Shyra J. Gardai, Peter D. Senter, Patrick J. Burke
Journal: Cancer Research (2023)

Abstract Novel payloads with orthogonal mechanisms of action (MOAs) to established ADC technologies are important for expanding the utility of antibody-drug conjugates (ADCs) in cancer treatment. Anthracyclines, a class of cytotoxic small molecules that include important clinical chemotherapeutics such as doxorubicin, have long been of interest to the ADC field due to their high potency and unique MOA. Interest in anthracyclines has increased in recent years due to their status as canonical inducers of immunogenic-cell death (ICD), a feature that may lead to more durable tumor regressions and increased synergy with immune checkpoint blockade. In this work, we investigate several drug-linkers based on oxidized derivatives of the highly potent anthracycline analogue PNU-159682. Resultant ADCs are potent and immunologically specific with linker-dependent bystander activity in co-culture cytotoxicity assays displaying heterogeneous antigen (Ag+/Ag-) expression. Rodent in vivo anti-tumor activity and tolerability are shown with significant differences emerging between the toxicity profile of the cleavable and non-cleavable analogues. In vitro, tumor cells treated with anthracycline ADCs showed key hallmarks of ICD including markers of endoplasmic reticulum (ER) stress and the induction of ICD damage-associated molecular patterns (DAMPs) such as HMGB1 and ATP. In vivo mouse xenograft studies show increased tumoral F4/80+ macrophage infiltration by IHC in anthracycline ADC treated animals relative to controls. ADCs delivering monomethyl auristatin E (MMAE) show comparable activity in ICD assays, confirming MMAE as an ICD inducing ADC payload alongside canonical inducers such as anthracyclines. Our results indicate there is a therapeutic window in rodents alongside ICD induction by anthracycline ADCs, positioning anthracyclines as a potentially impactful class of ADC payloads. Citation Format: Joseph Z. Hamilton, Kerry Klussman, Rebecca Mahzereh, Jessica Simmons, Michelle Ulrich, Shyra J. Gardai, Peter D. Senter, Patrick J. Burke. Oxidized anthracycline payloads induce anti-tumor immunogenic cell-death and show linker-dependent tolerability when delivered as ADCs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2013.
Abstract 1661: Heart-sparing ALK5 inhibitor for treatment of gastrointestinal and liver cancers
Authors: Andrew T. Miller, Qihui Jin, David Plouffe, Manny Corpuz, Evelyn Rodrigo, Tom Y.- Wu
Journal: Cancer Research (2023)

Abstract Transforming growth factor beta (TGFβ) signaling has been implicated in many cancers and fibrotic diseases. Recent pharmacological intervention has shown promising activities in preclinical models and early clinical trials. There are over 15 investigational agents targeting this pathway currently in the clinic, but none have been approved. In particular, small molecule TGFβ inhibitors targeting ALK5 (TGFβ type 1 receptor) have been limited by mechanism-based heart valve toxicity to low dose and intermittent dosing regimens. NEX002 is an oral liver-targeted ALK5 inhibitor with low heart exposure for the treatment of liver cancer and other gastrointestinal cancers with liver metastases. The compound was designed following drug design principles from known liver-specific drugs, such as the statins. In animals, NEX002 exerts preferential distribution (pharmacokinetic) and target inhibition (pharmacodynamic) in liver over the heart. NEX002 has demonstrated activity in several intrahepatic and subcutaneous tumor models, and significantly enhanced the durability of anti-tumor efficacy in combination with lenvatinib, a VEGFR inhibitor approved for the treatment of hepatocellular carcinoma. No heart valve toxicity was observed when benchmarked against galunisertib (systemic ALK5 inhibitor) in toxicity studies with repeated daily dosing. These data suggest that our liver-targeted/heart-sparing approach may allow more robust target engagement compared to systemic ALK5 inhibitors through higher dose or more frequent dosing. Citation Format: Andrew T. Miller, Qihui Jin, David Plouffe, Manny Corpuz, Evelyn Rodrigo, Tom Y.- Wu. Heart-sparing ALK5 inhibitor for treatment of gastrointestinal and liver cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1661.
Abstract 1435: A GABP dominant negative approach to targeting tumor cell immortality
Authors: Nicholas O. Stevers, Sara A. Collins, Samuel H. Wu, Noriyuki Kasahara, Joseph F. Costello
Journal: Cancer Research (2023)

Abstract Immortality is a hallmark of human cancer cells and therapeutic reversal is of great interest. Telomerase Reverse Transcriptase promoter (TERTp) mutations reactivate TERT expression, the rate limiting step in telomerase activity and cellular immortality. While prior telomerase blocking therapies lack tumor selectivity and were poorly tolerated, TERTp mutations and their regulation offer a unique opportunity for tumor specific reversal of cellular immortality. TERTp mutations are the most common non-coding mutation across all cancers, including glioblastoma (GBM), melanoma, urothelial carcinoma, and many others. The mutations generate a de novo E26 Transformation Specific (ETS) binding motif that recruits the GA-Binding Protein (GABP) multimeric complex to reactivate TERT expression. While GABP can form both a dimeric and tetrameric complex, we found that the tetrameric complex is responsible for reactivation of the mutant TERTp, suggesting selectively targeting the tetramer may induce telomere shortening and tumor cell death. However, through knocking out the tetramer, we found that the GABP dimer is sufficiently upregulated to maintain TERT expression. In the absence of the dimer and the tetramer isoform, many tumor cells senesce or undergo cell death. However, some escape this fate via upregulation of a second tetramer forming GABP paralogue that maintains TERT expression. Therefore, we devised a transactivation domain null GABP subunit that we hypothesized would act in a dominant negative manner to block the GABP dimer and both GABP tetramers. Introduction of the dominant negative construct into TERTp mutant GBM, meningioma, medulloblastoma, oligodendroglioma, and urothelial carcinoma cells significantly reduced TERT expression while not altering expression in TERTp wildtype GBM cells. Furthermore, the dominant negative is able to shorten telomere length in TERTp mutant GBM cells. While therapeutic targeting of the three GABP complexes seems particularly challenging, our initial dominant negative appears to do so. Ultimately the dominant negative could be delivered directly into tumors via clinically approved viral delivery systems such as retroviral replicating vectors. Citation Format: Nicholas O. Stevers, Sara A. Collins, Samuel H. Wu, Noriyuki Kasahara, Joseph F. Costello. A GABP dominant negative approach to targeting tumor cell immortality [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1435.
Abstract 1381: Reprogramming of iron metabolism confers ferroptosis resistance in ECM-detached cells
Authors: Jianping He, Abigail M. Abikoye, Brett P. McLaughlin, Ryan S. Middleton, Ryan Sheldon, Russell G. Jones, Zachary T. Schafer
Journal: Cancer Research (2023)

Abstract Cancer cells often acquire resistance to cell death programs induced by loss of integrin-mediated attachment to extracellular matrix (ECM). Given that adaptation to ECM-detached conditions can facilitate tumor progression and metastasis, there is significant interest in effective elimination of ECM-detached cancer cells. Ferroptosis is an iron dependent non-apoptotic cell death due to catastrophic accumulation of lipid peroxidation. While the mechanism that determines ferroptosis sensitivity has been extensively investigated in attached cells, how cells respond to ferroptosis under ECM detachment is largely unknown. Here, we find that ECM-detached cells are remarkably resistant to the induction of ferroptosis. While alterations in membrane lipid content are observed during ECM-detachment, it is instead fundamental changes in iron metabolism that underlie resistance of ECM-detached cells to ferroptosis. More specifically, our data demonstrate that levels of free iron are low during ECM-detachment due to changes in both iron uptake and iron storage. In addition, we establish that lowering the levels of iron storage proteins sensitizes ECM-detached cells to death by ferroptosis. Taken together, our data suggest that therapeutics designed to kill cancer cells by ferroptosis may be hindered by lack of efficacy towards ECM-detached cells. Citation Format: Jianping He, Abigail M. Abikoye, Brett P. McLaughlin, Ryan S. Middleton, Ryan Sheldon, Russell G. Jones, Zachary T. Schafer. Reprogramming of iron metabolism confers ferroptosis resistance in ECM-detached cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1381.